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Pilot Scale and Scale-Up :

Pilot Scale and Scale-Up Means ? :

Pilot Scale and Scale-Up Means ? Intermediate Batch scale Manufactures Drug Product By A Procedure Fully Represrntative Of And Simulatory To That Of Manufacturing Scale PILOT SCALE SCALE-UP Next to Pilot scale Process Of Increasing The Batch Size (Mixing) / Procedure For Applying The Same Process To Different Output Volumes ( Tabletting )

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Need of Scale-Up ? A well defined process A perfect product in laboratory and pilot plant But may fail in QA tests Because processes are scale dependent Processes behave differently on a small scale and on a large scale Scale-Up is necessary to determine the effect of scale on product quality

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Formulation related Indentification and control of critical components and other variables Equipment related Identification and control of critical parameters and operating ranges Production and Process related Evaluation, validation, and finalization of controls Product related Development and validation of reprocessing procedures Documentation Records and reports according to cGMP Objectives of the Scale-Up

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Examination of the Formula to determine ..... Ability to withstand batch scale Process modification Compatibility of the equipment with the formulation Cost factor Physical space required Market requirement Layout of the related functions Availability of the raw materials meeting the specifications

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Scale-Up ..... Should Adequately monitor the process To provide the assurance that the process is under control The product produced maintains the specified attributes originally intended

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Equipment selected based on processing characteristics of product Most economical, simplest and efficient The size should be relevant to production sized batches Ease of cleaning Time of cleaning EQUIPEMENT REQUIREMENT

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Process parameters should be evaluated and optimized. For example : Mixing Order of addition Mixing speed Mixing time Rate of addition etc., PROCESS EVALUATION

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Chemical weigh sheet Identify the chemicals Its quantity The order of using The sampling directions Process specifications Should be in understandable language In process and finished product specifications Proper documentation required MASTER MANUFACTURING PROCEDURE

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Validated cleaning procedures An orderly arrangement of equipment so as to ease material flow and prevent cross-contamination A well defined technology transfer system The use of competent, technically qualified personnel Adequate provision for training of personnel

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Scale-up Considerations For Tablets

Material/Powder Handling:

Material/Powder Handling Two primary concerns : Achieving reliable flow and maintaining blend uniformity. Segregation leads to poor product uniformity. Handling system : - Must deliver the accurate amount of the ingredient - Material loss should be less - There should be no cross contamination

Avoiding segregation …..:

Avoiding segregation ….. Modify the powder in a way to reduce its inherent tendency to segregate Change the particle size such that the active segregation mechanism becomes less dominant Change the cohesiveness of the powder such that the particles in a bed of powder are less likely to move independent of each other Modify the equipment to reduce forces that act to segregate the powder Change the equipment to provide remixing

Dry Blending:

Dry Blending Dry blend should take place in granulation vessel Larger batch may be dry blended and then subdivided into multiple sections for granulation. All ingredients should be free of lumps otherwise it causes flow problems. Screening and/or milling of the ingredients prior to blending usually makes the process more reliable and reproducible.

GRANULATION:

GRANULATION The weight of the material and the shear forces generated by granulation equipment. The use of multifunctional processors (significant in terms of space and manpower requirements). Viscosity of the granulating solution.

DRYING:

DRYING HOT AIR OVEN FLUIDIZED BED DRYER

Hot Air Oven:

Hot Air Oven Air flow Air Temperature Depth of the granulation on the trays Monitoring of the drying process by the use of moisture and temperature probes Drying times at specified temperatures and air flow rates for each product

Fluidized Bed Dryer:

Fluidized Bed Dryer Optimum Load Air Flow Rate Inlet Air Temperature Humidity of the Incoming Air

PARTICLE SIZE REDUCTION:

PARTICLE SIZE REDUCTION Sizing plays a key role in achieving uniformity. There are two ways of sizing : Particle size separation and Particle size reduction. Major Factor – Feed rate of the material. During scale up, overhead feeding equipment is incorporated to mimic large scale production.

SPECIALISED GRANULATION PROCEDURES:

Dry Blending and Direct Compression:

Dry Blending and Direct Compression The order of addition of components to the blender The blender load The mixing speed The mixing time The use of auxiliary dispersion equipment within the mixer The mixing action Compression force

Slugging (Dry Granulation):

Slugging (Dry Granulation) Forces used for slugging operation The diameter of the punches Subsequent sizing and screening operations

GRANULATION HANDLING AND FEED SYSTEM:

GRANULATION HANDLING AND FEED SYSTEM Evaluation of vacuum automated handling systems and mechanical systems Segregation : Due to static charges built up due to vacuum can alter material flow property The effect of above system on the content uniformity of the drug and on the particle size

COMPRESSION:

COMPRESSION Press speed Handling and compression characteristics (in the selection of a tablet press) Die filling rate Flow rate of granules Induced die feed systems (for high speed machines) – speed of feed paddles The clearance between the scraper blade and the die table Design and condition of the punches

Fluidized Bed Coating:

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Liquid Dosage Forms

SOLUTION:

SOLUTION Tank size (diameter) Impeller type Impeller diameter Rotational speed of the impeller Number of the impellers Number of baffles Mixing capability of impeller Clearance between impeller blades and wall of the mixing tank Contd …..

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Height of the filled volume in the tank Filtration equipment (should not remove active or adjuvant ingredients) Transfer system Passivation of stainless steel (pre reacting the SS with acetic acid or nitric acid solution to remove the surface alkalinity of the SS)

SUSPENSION:

SUSPENSION Addition and dispersion of suspending agents (Vibrating feed system at production scale) Hydration/Wetting of suspending agent Time and temperature required for hydration of suspending agent Mixing speeds (High speed lead to air entrapment) Selection of the equipment according to batch size Versator (to avoid air entrapment) Mesh size (should not filter out any of the active ingredients)

EMULSION:

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Semisolid Products

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Mixing equipment Motors (used to drive mixing system and must be sized to handle the product at its most viscous stage) Mixing speed Component homogenization Heating and cooling process Addition of active ingredients Product transfer Working temperature range (critical to the quality of the final product)

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Shear during handling and transfer from manufacturing to holding tank to filling lines Transfer pumps While choosing size and type of pump : Product viscosity Pumping rate Product compatibility with the pump surface Pumping pressure required should be considered

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Parenteral Products

PARENTERAL SOLUTION:

PARENTERAL SOLUTION It is liquid scale up task. Mixing is one of the important process to be scaled up. Large scale mixing -- Flow Small scale mixing -- Shear Geometric factors :- -- Diameter of the impeller (D) -- Diameter of the tank (T) -- Height of the liquid in the vessel (Z) -- Impeller speed

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Sterilization equipment Filtration equipment Pumps Packaging equipment also have to be scaled up.

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Biotechnology Derived Products

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The design and Scale-up of biological processes is very challenging. Parameters to be considered for scale-up of biotechnology products are : Bioreactor Operation Filtration Operation Centrifugation Chromatography Viral Clearance

FILTERATION OPERATION:

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Other variables used in scale-up work for filteration are : The length of the fibers (L) The fiber diameter (D) The number of fibers per cartridge (n) The density of the culture ( ρ ) The viscosity of the culture ( μ ) From these variables, scale-up parameters such as wall shear rate and its effect on flux are derived.

GEOMETRIC SIMILARITY:

MECHANICAL SIMILARITY:

MECHANICAL SIMILARITY Concerned with application of force to a stationary or moving system. Static similarity – It is the deformation of one body or structure to that of an other under constant stress. Kinematic similarity – Corresponding moving particles take similar path in the corresponding time interval. Dynamic similarity – Forces which accelerate or retard the motion of materials. Moving systems are dynamically similar when the ratio of all forces is equal. It is useful in the prediction of pressure drops, power consumption.

Systems exhibit mechanical similarity only if they are geometrically similar.:

NOTE Systems exhibit mechanical similarity only if they are geometrically similar.

THERMAL SIMILARITY:

THERMAL SIMILARITY It is concerned with flow of heat (by radiation, conduction, convection, or the bulk transfer of material). Geometrically similar systems are thermally similar when temperature difference bears constant ratio and in moving systems it must have Kinematic similarity.

CHEMICAL SIMILARITY:

CHEMICAL SIMILARITY It is concerned with the variation in chemical composition from point to point as a function of time. It is related to existence of comparable concentration gradients. It is dependent upon both thermal and Kinematic similarity.

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A thorough understanding of the integration of scale factors, facility design, equipment design and process performance is necessary for scale-up and process transfer.:

A thorough understanding of the integration of scale factors , facility design , equipment design and process performance is necessary for scale-up and process transfer. CONCLUSION

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What is the difference between Pilot Scale and Scale-Up? Outline the Pilot Plant Operation and give brief note on each . Enumerate the parameters that should be considered during the scale up of Tablet Coating ? Give a brief note on Scale-Up of Biotechnology-Derived Products and Parenteral Solutions . What are the steps involved in transfer of a formulation right from F&D to Production Facility ? FAQs